tbuckley/cabot-search huggingface dataset:
Abstract IA017: Anticipating, tracking, and targeting new prostate cancer lineages driven by treatment pressures
Authors: Peter S. Nelson
Journal: Cancer Research (2023)

Abstract Prostate cancer is notable for the near universal dependence on signaling pathways regulated by the androgen receptor (AR). For decades, this feature has served as the major focal point for prostate cancer treatment. However, in the setting of advanced metastatic disease, AR pathway repression is not curative and treatment resistance occurs universally. Emerging mechanisms of resistance to AR-directed therapy involve changes in tumor cell phenotypes where AR-regulated differentiation programs are repressed and new lineage programs are activated. This presentation will discuss the lineage types that have been recognized in model systems and in clinical tumors, describe approaches to monitor patients for the development/emergence of new therapy-induced lineages, and discuss treatment strategies that target new characteristics and vulnerabilities that accompany these new lineages. Citation Format: Peter S. Nelson. Anticipating, tracking, and targeting new prostate cancer lineages driven by treatment pressures [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA017.
Abstract B047: Characterizing the landscape of extracellular vesicles from prostate cancer cell lines
Authors: Megan Ludwig, Zoi Sychev, Abderrahman Day, Hannah Bergom, Justin Hwang, Justin M. Drake
Journal: Cancer Research (2023)

Abstract Multiple subtypes of prostate cancer can emerge in the advanced stages of disease, such as androgen receptor (AR+), AR indifferent with neuroendocrine features (AR-/NE+), and those without AR or NE features (double negative, DN). These latter variants are particularly aggressive and incredibly lethal. Extracellular vesicles (EVs), also known as exosomes, are small particles that are important mediators of cell-cell communication and have been nominated as potential biomarkers of disease state. We hypothesized that the proteome of extracellular vesicles contains enough information about their originating cell that they can distinguish between prostate cancer subtypes. To address this, we isolated EVs from prostate cancer cell lines of differing subtypes – AR+ (LNCaP, LNCaP95, C4-2, 22RV1), AR-/NE+(NCI-H660, EF1, LASCPC-01), and AR-/NE- (PC3, DU145) – and prepared the EV proteome for quantitative mass spectrometry analysis. This identified 2,000+ proteins in the EVs for each cell line. From our analysis, we found that the EVs from cell lines of similar subtypes clustered together with several hundred proteins statistically different between the three groups. Interestingly, we also found that EVs contained enough protein information to utilize already developed gene signature scores for AR or NE activity. EVs isolated from the AR-/NE+ cell line NCI-H660 scored over 90% with a 121 gene NE signature and included proteins such as SYP, CHGA, and UCHL1. EVs from all the AR+ cell lines displayed &amp;gt;80% AR activity that was driven by high expression of PSA and STEAP1. This supports the idea that we can use the proteome of tumor-derived EVs to identify signature molecular markers that are already known to the field to develop liquid-based biomarker assays. Further work in the clinical setting is needed to evaluate the ability for EVs to be specific, informative biomarkers for prostate cancer disease status. Citation Format: Megan Ludwig, Zoi Sychev, Abderrahman Day, Hannah Bergom, Justin Hwang, Justin M. Drake. Characterizing the landscape of extracellular vesicles from prostate cancer cell lines [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B047.
Abstract B013: KLF5 drives basal cell identity to promote prostate cancer lineage plasticity
Authors: Samuel P. Pitzen, Yinjie Qiu, Sarah Munro, Scott M. Dehm
Journal: Cancer Research (2023)

Abstract The purpose of this study was to characterize the phenotypes and drivers of therapy-induced lineage plastic castration resistant prostate cancer (CRPC). Since the majority of primary prostate cancer presents with a luminal cell identity, which relies on androgen receptor (AR) signaling for growth and survival, AR-targeted therapies have become an effective method of slowing progression. However, CRPC cells can develop resistance through reduced or lost dependence on AR. These cells can transition their identity to neuroendocrine CRPC (NEPC), which lacks AR and expresses neuroendocrine lineage specific markers like chromogranin A. More frequently, these cells display transition to a cell identity that lacks AR and neuroendocrine markers and has been termed double-negative CRPC (DNPC). Identifying effective therapeutic targets to treat or prevent DNPC remains a significant clinical challenge. By utilizing prostate cancer cell lines, patient derived xenografts (PDX), and publicly available data from clinical CRPC specimens, we have identified an upregulation in basal cell identity in a subset of CRPC in response to AR-targeted therapies. Additionally, we show that the stem cell transcription factor KLF5, which is highly expressed in healthy prostate basal cells, is uniquely upregulated in CRPC subtypes displaying basal cell identity. In a cell line model of DNPC, we found that knockdown of KLF5 decreased the expression of genes that define basal cell identity. From these results, we conclude that AR-targeted therapies, while effective at targeting luminal-like adenocarcinoma, promote upregulation of KLF5 which can drive a basal cell identity and AR independence. These studies nominate KLF5 signaling as a potential therapeutic target to block the emergence of basal identity, inhibit prostate cancer lineage plasticity, and increase the durability of AR-targeted therapies. Citation Format: Samuel P. Pitzen, Yinjie Qiu, Sarah Munro, Scott M. Dehm. KLF5 drives basal cell identity to promote prostate cancer lineage plasticity [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B013.
Abstract IA003: Evolution of AR gene structure during prostate cancer progression
Authors: Scott M Dehm
Journal: Cancer Research (2023)

Abstract Castration-resistant prostate cancer (CRPC) emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. Our laboratory has implemented DNA sequencing approaches to identify genomic mechanisms contributing to CRPC in prostate cancer cell lines, patient-derived xenografts (PDXs), and clinical specimens. These approaches have revealed AR as one of the most frequently-rearranged genes in CRPC. However the patterns of AR gene rearrangements observed between patients and even between anatomically distinct metastases within a single patient are remarkably complex and heterogeneous. To address this complexity, we analyzed a cohort of prostate cancer specimens using linked-read DNA-sequencing. This approach found that a subset of clinical CRPC metastases had accumulated complex AR rearrangements in conjunction with very high AR copy number, a phenomenon that also occurred in PDX models grown under selective pressure of castration. Using orthogonal approaches of optical genome mapping and fluorescence in situ hybridization, we found that AR residing on extrachromosomal circular DNA (eccDNA) was an underlying mechanism. This study identifies eccDNA as an engine for accumulation of AR gene copy number and structural complexity during CRPC progression. Citation Format: Scott M Dehm. Evolution of AR gene structure during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA003.
Abstract IA019: Tumor microenvironment modulation is critical for cellular immunotherapy efficacy
Authors: Tanya B Dorff, M Suzette Blanchard, John Murad, Lauren Adkins, Gaurav Dhaploa, Stephen Forman, Saul Priceman
Journal: Cancer Research (2023)

Abstract Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of prostate cancer, among other solid tumors. However the role of lymphodepletion was uncertain for application outside of heme malignancies. We studied the effect of chemotherapy preconditioning on the tumor immune microenvironment along with the impact on CAR-T cell activity. Methods: Immunocompetent mice bearing RM9 prostate tumors lentivirally transduced to express human prostate stem cell antigen (PSCA) and treated with PSCA targeted CAR T cells alone, or after 100 mg/kg cyclophosphamide (Cy). Tumors were evaluated for immune cell subsets infiltration in addition to clinical response. As part of a phase 1 dose escalation trial patients received 100 M PSCA-targeted CAR T cells, manufactured at City of Hope’s cGMP facility, alone or after Cy. CAR T persistence and cytokine levels were evaluated by flow cytometry and luminex, respectively. Results: CAR T cells alone had minimal anti-tumor effect in immune competent mice. Cy was associated with increased CD11c+ DCs and reduced CD206+ M2 macrophages in the tumors. With Cy pre-conditioning followed by infusion of PSCA-CAR T cells, over 40% of mice had complete response (CR) and rejected rechallenge of tumor. 10-fold greater T cell infiltration was noted in tumors after Cy preconditioning, with lesser increase and no anti-tumor effect noted with Cy + mock CAR T cells. In the phase 1 human trial greater CAR T cell expansion and cytokine induction were noted with Cy + PSCA-CAR T compared to PSCA-CAR T alone. Conclusion: Cy functions as a modifier of the prostate cancer tumor microenvironment, facilitating CAR T cell infiltration and expansion. This has resulted in greater activity of PSCA-CAR T cells both in murine models and preliminary human testing. Further study of manipulations to optimize the tumor immune microenvironment will likely be important to maximizing efficacy of cellular immunotherapy in prostate cancer. Citation Format: Tanya B Dorff, M Suzette Blanchard, John Murad, Lauren Adkins, Gaurav Dhaploa, Stephen Forman, Saul Priceman. Tumor microenvironment modulation is critical for cellular immunotherapy efficacy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA019.
Abstract A058: Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling
Authors: Maxim Kobelev, Dwaipayan Ganguli, Takeshi Namekawa, Amina Talal, Joshua Scurll, Amina Zoubeidi
Journal: Cancer Research (2023)

Abstract Background: Roughly 20% of late stage prostate cancer patients display a lineage conversion from typical androgen receptor (AR) driven castrate resistant prostate cancer (CRPC) to a particularly lethal neuroendocrine prostate cancer (NEPC) phenotype as a result of AR pathway inhibition (ARPI). Notably, the mutational landscape of CRPC and NEPC is quite similar, suggesting that epigenetic changes may guide this lineage conversion. Our objective was to explore changes in active epigenetic marks with a particular focus on super-enhancers (SEs) and identify factors that regulate these active regions during lineage plasticity. Methods: We performed ChIP-seq for H3K27ac, H3K4me3 and various TFs in our CRPC and ENZ resistant (ENZR) NEPC-like cell models. We leveraged publicly available H3K27ac data in cell lines as well as PDX models to validate our findings. RNA-seq was integrated with our ChIP-seq results to create a signature which we applied to patient data sets. GIGGLE analysis was used to identify candidate factors at SEs. Results: CRPC and NEPC showed similar active marks at promoters however, enhancer elements were significantly remodeled. We observed extensive remodeling of SEs in our ENZR model compared to CRPC and these unique regions showed greater H3K27ac signals in other ENZR models such as NCI-H660. SE linked genes are associated with stemness pathways and are strongly upregulated as a result of ARPI in vitro, and in vivo. Factor enrichment analysis of these regions showed enrichment for MAX and MYC family binding similar to small cell lung cancer cell lines. ChIPseq for MYC and MAX in our cell models revealed an expansion of MAX binding and contraction of MYC binding in our ENZR model compared to CRPC. In particular, we saw increased binding of MAX at plasticity SEs without MYC suggesting an interaction with MYCL or other factors since MYCN is not expressed in our models. Conclusions: This work improves our understanding of the epigenetic changes that occur during lineage plasticity and ARPI resistance. SE analysis in our models suggests that MAX may be activating these regions with MYCL or independently of the MYC family. MYCL expression is upregulated in NEPC and has higher expression than MYCN suggesting a potential role during lineage plasticity. Citation Format: Maxim Kobelev, Dwaipayan Ganguli, Takeshi Namekawa, Amina Talal, Joshua Scurll, Amina Zoubeidi. Lineage plasticity is associated with an altered MAX cistrome through super-enhancer remodeling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A058.
Abstract B022: Dopamine receptor antagonists sensitize prostate cancer cells to androgen targeted therapy
Authors: Le Zhang, Sandrine Billet, Gabrielle Gonzales, Krizia Rohena-Rivera, Hayato Muranaka, Yeonjoo Lee, Sungyong You, Edwin M. Posadas, Neil A. Bhowmick
Journal: Cancer Research (2023)

Abstract Prostate cancer (PC) incidence is predicted to reach around 2 million new cases by 2040. High fat diet and obesity are associated with the progression and mortality of PC. Palmitate is a common saturated fatty acid, it induces endoplasmic reticulum (ER) stress that activates the unfolded protein response (UPR). Failure to adapt to ER stress results in apoptosis to eliminate irreversibly damaged cells. Master regulator analysis found that Arid5a was a master regulator of saturated fat-induced cellular responses. We confirmed that exogenous palmitate activated ARID5a/UPR signaling, while further activation could induce apoptosis. In trying to determine the mechanism of ARID5a activation, we found that palmitate promoted the expression of dopamine receptors 2 and 3 (DRD2, DRD3) in prostate cancer cell lines. Since high diets have other deleterious effects, we tested the role of dopamine receptor antagonists (e.g. ONC201, prochlorperazine) and found them to serve as UPR activators, inducing apoptosis in ARCaPM and 22Rv1 cells. As our data showed that ARID5a expression could inhibit prostate-specific membrane antigen (PSMA), we next tested the role of dopamine receptor antagonists in sensitizing castrate resistant cells to androgen targeted therapy. Both castrate resistant cell lines (22Rv1 and ARCaPM) were found to be made sensitive to enzalutamide by dopamine inhibition, inhibiting cell proliferation and promoting apoptosis. These findings are especially compelling since dopamine receptor antagonist, prochlorperazine, is a commonly prescribed anti-nausea drug and ONC201 is currently in clinical trials meeting safety endpoints. Preclinical studies in mouse models of castrate resistant PC support the administration of such dopamine receptor antagonists with androgen targeted therapy to sensitize otherwise refractile tumors by the promotion of ER stress pathway, addressing a common adaptation mechanism employed by cancer cells. Citation Format: Le Zhang, Sandrine Billet, Gabrielle Gonzales, Krizia Rohena-Rivera, Hayato Muranaka, Yeonjoo Lee, Sungyong You, Edwin M. Posadas, Neil A. Bhowmick. Dopamine receptor antagonists sensitize prostate cancer cells to androgen targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B022.
Abstract B064: ONECUT2 inhibition, a potential treatment for lethal prostate cancer
Authors: Brad Gallent, Chen Qian, Avradip Chatterjee, Madhusudhanarao Katiki, Ramachandran Murali, Michael R Freeman
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the most common cancer and the second most lethal cancer in men, claiming over 30,000 lives each year in the US alone. These PCa patient deaths are typically due to castration-resistant PCa (CRPC) which is resistant to androgen deprivation therapy, androgen receptor signaling inhibitors, and chemotherapies. Our group and others have shown that the transcription factor ONECUT2 (OC2) is a critical driver of CRPC. We have discovered a low molecular weight inhibitor of OC2 (OC2i), known as CSRM617, which inhibits metastatic PCa in cell culture (IC50 of 5-15 uM depending on cell line used) and effectively treats xenograft CRPC tumors in mouse models. We have developed a large series of these OC2i based on the CSRM617 scaffold. A thorough understanding of how these OC2i bind to and inhibit OC2 function are imperative to developing them into a clinically viable treatment option. Our recent work shows CSRM617 binds Fe and that this Fe:CSRM617 complex is necessary in order to inhibit OC2 binding of DNA. We have solved the crystal structure of OC2 bound to its conjugate DNA response element, demonstrating their atomic-level interactions. We are working towards solving a crystal structure of these OC2i bound to OC2 in order understand their specific interactions and make rational modifications to the chemical scaffold for improvements in binding affinity and pharmacokinetic properties. Citation Format: Brad Gallent, Chen Qian, Avradip Chatterjee, Madhusudhanarao Katiki, Ramachandran Murali, Michael R Freeman. ONECUT2 inhibition, a potential treatment for lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B064.
Abstract A047: Panorama of complex structural variants in primary localized prostate cancer
Authors: André Olsen, Francesco Favero, Yilong Li, Etsehiwot Girma, Breon Feran, Tony Papenfuss, Kristian Helin, Jüri Reimand, Joachim Weischenfeldt
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is a hormone-driven disease characterized by an abundance of structural variations (SV). Deconvolving the SV patterns can both inform on prior mutational processes leading to cancer, and be leveraged to identify patients with more aggressive disease. Under the auspices of the Pan Prostate Cancer Group (PPCG) consortium, we used whole genome sequencing of 812 treatment naive PCa patients to study both simple and complex SVs. In total, we classified 15,708 simple SVs and 1,448 complex SV events. Complex SVs such as chromothripsis, chromoplexy and templated insertion were found in more than half of the cohort. We also detected tandem duplicator phenotype (TDP) in a subset of the patients associated with CDK12 aberrations. Breakpoint recurrence analysis of driver genes revealed disruption of e.g. PTEN and formation of TMPRSS2-ERG fusion genes frequently coincide with occurrences of specific complex SV types, suggesting specific mutational processes driving these alterations of these cancer genes. Based on the simple and complex SV classifications we extracted six SV signatures, including two TDP-like signatures, distinct deletion-specific SV signatures and a signature characteristic of AR binding sites. We found signatures associated with disease markers, including Gleason score, risk scores, as well as age. Together, these findings provide insights into mechanisms driving SV formation and driver gene alterations in PCa, with potential for identifying markers of aggressive disease. Citation Format: André Olsen, Francesco Favero, Yilong Li, Etsehiwot Girma, Breon Feran, Tony Papenfuss, Kristian Helin, Jüri Reimand, Joachim Weischenfeldt. Panorama of complex structural variants in primary localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A047.
Abstract B026: PIM kinases regulates tumor associated macrophage survival and inflammatory signaling
Authors: Amber N. Clements, Noel A. Warfel
Journal: Cancer Research (2023)

Abstract Prostate tumors are highly infiltrated by immunosuppressive tumor associated macrophages (TAMs). TAMs secrete various factors that promote tumor progression and suppress antitumor immunity, making them a promising therapeutic target. PIM kinases are serine/threonine kinases that are overexpressed in several tumor types including prostate cancer. PIM regulates many signaling pathways that promote cell proliferation and cell survival. However, the role of PIM in macrophages is not well understood. Macrophages express NLRP3, a cytosolic innate immune sensor, that forms a complex with ASC and caspase-1 termed the inflammasome. Activation of the inflammasome leads to release of proinflammatory cytokines including IL-1β and induces pyroptotic cell death. We hypothesize that PIM promotes macrophage survival by suppressing inflammasome activation. To test our hypothesis, we treated mouse bone marrow derived macrophages (BMDMs) with PIM447, a pan-PIM kinase inhibitor, and activated the inflammasome via lipopolysaccharide (LPS) and ATP stimulation. Preliminary data demonstrates that PIM inhibition in BMDMs promotes increased inflammasome activation as indicated by increased cleaved caspase-1 and increased IL-1β secretion. Recent studies have demonstrated that PIM kinases promote immune evasion through the modulation of both tumor cells and immune cells within the tumor microenvironment. We hypothesize that PIM kinase promotes TAM survival leading to increased immunosuppression and immunotherapy resistance in prostate cancer. We treated immunocompetent mice injected with MyC-Cap prostate cancer cells with PIM447. PIM inhibition decreased tumor growth and decreased the presence of tumor associated macrophages. In summary, the results of these studies suggest that PIM plays an important role in regulating macrophage survival and inflammatory signaling. Furthermore, PIM may be a potential target to enhance the efficacy of immunotherapies for the treatment of prostate cancer. Citation Format: Amber N. Clements, Noel A. Warfel. PIM kinases regulates tumor associated macrophage survival and inflammatory signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B026.
Re: Jean-Nicolas Cornu, Paul Zantek, Glyn Burtt, et al. Minimally Invasive Treatments for Benign Prostatic Obstruction: A Systematic Review and Network Meta-analysis. Eur Urol. 2023;83:534–47
Authors: Carlos Gustavo Trujillo, Sebastián Peña Rodríguez, Cesar Diaz Ritter
Journal: European Urology (2023)